Systematic Review of the Efficacy and Safety of Shuxuening Injection in the Treatment of Unstable Angina

The aim of this study was to systematically review the efficacy and safety of Shuxuening injection combined with conventional Western medicine in the treatment of unstable angina. Randomized controlled trials of Shuxuening injection combined with conventional Western medicine in the treatment of unstable angina were searched by the computer system from PubMed, EMBASE, Cochrane Library, VIP, CNKI, Wanfang Database, and Chinese Biomedical Database since the establishment of the database until June 2020, according to the inclusion and exclusion criteria for the selection of literature, using Rev Man5.3 Meta-analysis Software. The 28 randomized controlled trials were included, with a total of 3,127 patients. Meta-analysis results showed that Shuxuening injection combined with conventional western medicine was effective in improving the clinical efficacy of angina pectoris (RR = 1.23, 95% CI [1.19, 1.27], P<0.00001), improvement of ECG (RR = 1.31, 95% CI [1.23, 1.40], P < 0.00001), reduction of angina pectoris attack frequency (MD = −1.28, 95% CI [−1.88, -0.67], P < 0.0001), duration of angina (MD = −3.36, 95% CI [−3.69, −3.03], P < 0.00001), nitroglycerin dosage (MD = -0.39, 95% CI [−0.65, −0.13], P = 0.003), C-reactive protein (MD = −2.72, 95% CI [−3.41, −2.03], P < 0.00001), BNP (MD = −23.33, 95% CI [−27.87, −18.79], P < 0.00001), lower triglycerides (MD = −0.72, 95% CI [−1.05, −0.38], P < 0.0001), total cholesterol (MD = −1.39, 95% CI [−1.84, −0.94], P < 0.00001), and LDL cholesterol (MD = -1.20, 95% CI [−2.12, −0.29], P = 0.01) which is better than that of control group. The effect on raising HDL cholesterol was comparable between the two groups (MD = 0.49, 95% CI [−0.06, 1.04], P = 0.08) and the incidence of adverse reactions to differences had no statistical significance (RR = 0.99, 95% CI [0.54, 1.81], P = 0.97). The Shuxuening injection combined with conventional Western medicine in the treatment of unstable angina has clear efficacy and a certain degree of safety, so it is recommended for clinical application.


Introduction
Unstable angina (UA) is an acute coronary syndrome between stable angina and acute myocardial infarction [1], which is mainly manifested as pain in the anterior cardiac region and posterior sternum. Its instability is mainly affected by native coronary artery lesions, and it is characterized by a progressive exacerbation of angina symptoms and prolonged duration of pain. rombosis is mainly caused by the rupture of atherosclerotic plaques or the erosion of the mural walls in coronary arteries [2,3]. e effective treatment of unstable angina can improve the survival rate and quality of life of the patients. Western medicine treatment mainly includes treating stable plaque, using antiplatelet and antithrombotic drugs, reducing myocardial injury brought about by ischemia and reperfusion, and preventing the progression of coronary atherosclerosis. With the popularity of traditional Chinese medicine, it plays a more and more important role in cardiovascular emergencies. e core theory of traditional Chinese medicine is the overall concept and treatment based on syndrome differentiation. It is supposed that it would have an excellent long-term efficacy, complementary with Western medicine treatment, giving full play to each other's advantages and improving the survival rate and quality of life of patients.
e Shuxuening injection is a prescribed herbal medicine of Ginkgo biloba extract; EGb aqueous solution is made by sterilization, with the main effective components such as flavonoid glycosides and terpenoid lactone active substances, including quercetin, galangal, different rat Li Su, Ginkgo biloba lactone, and Ginkgo lactone [4], to relax coronary artery, improve microcirculation, enhance body hypoxia tolerance, and reduce blood viscosity. However, the most clinical studies were clinical experience summary, lacking prospective trial with large sample size, and their pharmacological active components, and pharmacological mechanism still needs more studies to illustrate. In this study, the efficacy and safety of Shuxuening injection combined with conventional Western medicine in the treatment of unstable angina were systematically evaluated to clear the clinical efficacy of Shuxuening injection.

Methods
e meta-analysis followed the standard set of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). e protocol for this study was registered with CRD42021223531.

Literature Sources.
Randomized controlled trials of Shuxuening injection combined with conventional Western medicine in the treatment of unstable angina were searched by the computer system from PubMed, EMBASE, Cochrane Library, VIP, CNKI, Wanfang Database, and Chinese Biomedical Database since the establishment of the database until June 2020. To find out which words are used in China, Shuxuening injection, unstable angina, and any word in English are searched using the search terms "Shuxuening injection" and "Unstable angina."

Inclusion Criteria
(1) Study type: a clinical randomized controlled trial of Shuxuening injection combined with conventional Western medicine in the treatment of unstable angina was conducted.

Exclusion
Criteria. e intervention measures did not meet the inclusion criteria, the diagnosis was not clear, and the course of treatment was not clear; the experimental group only used Shuxuening injection or Western medicine compared with the control group, and the control group used other proprietary Chinese medicine; the outcome indicators did not include any other adverse reactions.
2.4. Literature Screenings, Data Extraction, and Methodological Quality Evaluation. Two investigators independently read the full text of the literature to extract relevant information. e information extraction included the basic information of the literature, intervention methods, risk of bias assessment (type of study design, randomisation method, allocation concealment, blinding, completeness of data information, and outcome reporting), relevant outcome indicators, and adverse effects. When the two parties disagreed on the inclusion of the literature, the discussion was referred to a third party to judge the final literature for information extraction. e included literature was evaluated against the Cochrane Handbook [5] risk of bias assessment tool for clinical randomised controlled trials with entries on randomisation methods, allocation concealment, blinded implementation, outcome data completeness, selective reporting, and other sources of bias.

Statistical
Treatments. RevMan 5.3 Software was used only for the statistical analysis of the included literature review on research data. If significant heterogeneity was found in the experimental results (I 2 ≥ 50%), the randomeffects model was used only for the meta-analysis. If the experimental results showed good homogeneity (I 2 < 50%), the fixed-effects model was used for the metaanalysis. e risk ratio (RR) was used as the combined statistic for the meta-analysis, while the mean difference (MD) was used as the statistic for the meta-analysis. If more than 10 references were included in a specified outcome indicator, a funnel plot was used to analyze whether there was publication bias.

Literature Retrieval.
A total of 330 references were retrieved. e titles retrieved from various databases were imported into NoteExpress 3.2.0 Software. A total of 28 titles were finally included after screening . e literature screening flow chart and results are shown in Figure 1.

Quality Evaluation of Included Literature.
e works of literature included in this systematic review were evaluated using the Cochrane Handbook. A total of 28 studies were included, 4 studies [10,12,13,18] were grouped using the random number table method, the remaining 24 studies mentioned randomisation but did not specifically describe it, none of the included literature mentioned allocation concealment or blinding, none of the included literature had case loss or dropouts, all studies had complete data, and specific evaluation information on risk of bias is shown in Figure 2.

Frequency of Angina Attack.
ere were 5 articles [8,10,13,26,27] that observed the frequency of angina, and the heterogeneity test showed that there was significant heterogeneity among the results of studies (P < 0.00001, I 2 � 92%); therefore, a random-effects model was used for the meta-analysis, and the results showed a statistically significant difference (MD � −1.28, 95% CI [−1.88, −0.67], P < 0.0001), suggesting that the Shuxuening injection combined with conventional Western medicine in patients with lower frequency of angina attack effect is better than that in the control group, as shown in Figure 3.

Duration of Angina Attack.
ere were 5 studies [6,8,10,13,27] that observed the duration of angina attack. e heterogeneity test (P � 0.37, I 2 � 6%) indicated that there was small heterogeneity between the studies; therefore, a fixedeffects model was used for the meta-analysis, and the results showed a statistically significant difference (MD � −3.36, 95% CI [−3.69, −3.03], P < 0.00001), suggesting that the Shuxuening injection combined with conventional Western medicine in patients with reduced duration of angina attack effect is better than that in the control group, as shown in Figure 4.

Nitroglycerin Dosage.
3 studies [17,22,27] observed the dosage of nitroglycerin. e heterogeneity test (P � 0.55, I 2 � 0%) indicated that there was small heterogeneity between the studies; therefore, a fixed-effects model was used for the meta-analysis, and the results showed a statistically significant difference (MD � −0.39, 95% CI [−0.65, −0.13], P � 0.003), suggesting that the Shuxuening injection combined with conventional Western medicine in patients with less dosage of nitroglycerin effect is better than that in the control group, as shown in Figure 5.

Blood
Fat. 3 studies [11,16,29] observed the triglyceride (TG), and the heterogeneity test showed that there was significant heterogeneity among the results of studies (P < 0.0001, I 2 � 89%); therefore, a random-effects model was used for the meta-analysis, and the results show a statistically significant difference (MD � −0.72, 95% CI [−1.05, −0.38], P < 0.0001), suggesting that the Shuxuening injection combined with conventional Western medicine in Retrieval literature n=330, PubMed n=0, Cochrane Library n=0, EMbase n=0, CNKI n=102, chinese biomedical literature database n=13, VIP n=79, Wanfang n=136 A er screening repeated references, n=154 Review class n=32 Animal experiment class n=6 Uncorrelated studies n=64 Non-randomized controlled trials n=6 Inconsistent intervention measures n=18 Literature was obtained through preliminary screening n=52 Studies included in quantitative synthesis (Meta-analysis) n=28 Evidence-Based Complementary and Alternative Medicine     Evidence-Based Complementary and Alternative Medicine patients with lower triglycerides effect is better than that in the control group; 3 studies [11,16,29] observed the total cholesterol (TC), and the heterogeneity test showed that there was significant heterogeneity among the results of studies (P < 0.0001, I 2 � 89%); therefore, a random-effects model was used for the meta-analysis, and the results show a statistically significant difference (MD � −1.39, 95% CI [−1.84, −0.94], P < 0.00001), suggesting that the Shuxuening injection combined with conventional Western medicine in patients with lower total cholesterol effect is better than that in the control group; 3 studies [11,16,29] observed the lowdensity lipoprotein cholesterol (LDL-C), and the heterogeneity test showed that there was significant heterogeneity among the results of studies (P < 0.00001, I 2 � 98%); therefore, a random-effects model was used for the meta-analysis, and the results showed a statistically significant difference (MD � −1.20, 95% CI [−2.12, −0.29], P � 0.01), suggesting that the Shuxuening injection combined with conventional Western medicine in patients with lower LDL cholesterol effect is better than that in the control group; 3 studies     Evidence-Based Complementary and Alternative Medicine [11,16,29] observed the high-density lipoprotein cholesterol (HDL-C), and the heterogeneity test showed that there was significant heterogeneity among the results of studies (P < 0.00001, I 2 � 99%); therefore, a random-effects model was used for the meta-analysis, and the results showed no significant statistical significance (MD � 0.49, 95% CI [−0.06, 1.04], P � 0.08), suggesting that the Shuxuening injection combined with conventional Western medicine had the same effect on raising high-density lipoprotein cholesterol as the control group, as shown in Figure 8.

C-Reactive
Protein. 9 studies [8, 10, 11, 13-16, 18, 26] observed the C-reactive protein, and the heterogeneity test showed that there was significant heterogeneity among the results of studies (P < 0.00001, I 2 � 88%); therefore, a random-effects model was used for the meta-analysis, and the results showed a statistically significant difference (MD � −2.72, 95% CI [−3.41, −2.03], P < 0.00001), suggesting that the Shuxuening injection combined with conventional Western medicine in improving patients with the role of C-reactive protein is superior to that in the control group, as shown in Figure 9. [8,10,13,18] observed the brain natriuretic peptide. e heterogeneity test (P � 0.99, I 2 � 0%) indicated that there was small heterogeneity between the studies; therefore, a fixedeffects model was used for the meta-analysis, and the results showed a statistically significant difference (MD � −23.33, 95% CI [−27.87, −18.79], P < 0.00001), suggesting that the Shuxuening injection combined with conventional Western medicine in patients with reducing effect of brain natriuretic peptide is superior to that in the control group, as shown in Figure 10.

Risk Assessment of Bias.
For more than 10 of the included works of literature, the risk of publication bias was assessed. e funnel plot of clinical efficacy and ECG improvement outcome index of angina pectoris was observed. e results showed the incomplete symmetry between left and right, suggesting the risk of publication bias, which may

Research Results.
e main purpose of this study is to observe the clinical efficacy of Shuxuening injection in the treatment of unstable angina pectoris. e results showed that the integrative therapy was better than the solo conventional Western medicine in the unstable angina including the improvement of clinical curative effect and the reduction in the frequency of angina, angina duration, dosage of nitroglycerin, CRP, the BNP, lower triglyceride, total cholesterol, and low-density lipoprotein cholesterol.
ere is no significant difference in the incidence of adverse reactions. e clinical application of the integrative therapy in the treatment of unstable angina has clear efficacy and certain safety, providing more evidencebased evidence for the clinical application of Shuxuening injection in the future.

Research Significance.
e Shuxuening injection consists of the active components of Ginkgo leaf extract, which include flavone glycosides and terpenoids, and it can affect oxidation reaction, remove oxide free radical, improve blood flow state, inhibit platelet aggregation, and promote vascular smooth muscle relaxation [34]. e Shuxuening injection with multicomponents and multi-targets is an encouraging complementary to the Western medicine treatment in the unstable angina, especially to improve the survival rate and quality of life of patients. e adverse reactions of the integrative therapy were recorded in detail to help the clinical practice to prescribe.  Evidence-Based Complementary and Alternative Medicine

Limitations of the Study.
Our study is to evaluate the efficacy and safety of the integrative therapy in the treatment of unstable angina; meanwhile, it also has the following limitations: firstly, in 28 papers, only four studies were allocated using a random number table, and the rest of the 24 studies just mentioned the randomization without description. ere is no mention of allocation concealment and blinding in any of the included literature. All studies have no shedding or withdrawal. Secondly, most of the included studies were single-center randomized controlled studies, and the sample size was small. Only one study had a large sample size of 500 patients, but the calculation method of the sample size was not explained. irdly, conventional Western drugs were not described in detail in the included studies, which attributed to the study heterogeneity.

inking about the Future.
Investigators need to include high-quality clinical randomised controlled trials in future.
at is a key factor to improve the level of evidence. For the implementation of specific solutions to clear the random method, estimation of sample size, allocation concealment and blinding, attrition bias, and records of the adverse reactions during the study period should be paid more attention. e clinical study register is important too. TCM treatment should be based on syndrome differentiation, and TCM syndrome types should be specifically stipulated in the inclusion criteria so as to more improve the quality of life and prognosis of patients.

Conclusion
It is concluded that the Shuxuening injection combined with conventional Western medicine could improve the onset of unstable angina frequency, reduce the dosage of nitroglycerin, and improve ECG, the blood lipid, CRP, and BNP, but the quality of all included studies was low, so the more higher quality of clinical randomized controlled trials will be needed to further demonstrate the validity of Shuxuening injection combined with conventional Western medicine in the unstable angina.
Data Availability e data are available from PubMed, EMBASE, Cochrane Library, VIP, CNKI, Wanfang Database, and China Biomedical Database.

Conflicts of Interest
e authors declare no conflicts of interest regarding the publication of this article.